An adverse drug reaction (ADR) is an undesired and unintended effect of a drug. In particular, an adverse drug reaction occurs at doses used for prophylaxis, diagnosis or therapy. According to a widely cited meta-analysis, ADRs were ranked between the fourth and sixth most common cause of death (Lazarou et al., JAMA, 279(15):1200-1205, 1998). Cutaneous ADRs account for about 2-3% of all hospital admissions (Bigby et al., JAMA, 256(24):3358-3363, 1986). They range from mild maculopapular (MPE), with increasing severity, to life-threatening ADRs, such as hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN; Lyell's syndrome). The mortality rate of the latter can be as high as 40%.
HSS is characterized by multi-organ involvements (e.g. hepatitis or nephritis) accompanied with systemic manifestations (e.g. fever, arthragis, eosinophilia and lymphadenopathy) in additional to skin rashes (Roujeau et al., N. Engl. J. Med., 331:1272-1285, 1994). SJS and TEN are immune-complex-mediated hypersensitivity disorders characterized by rapid development of blistering exanthema of purpuric macules and target-like lesions accompanied with mucules involvement and skin detachments (Roujeau et al. J Invest Dermatol, 1994, 102:28S-30S). They are caused mostly by drugs, such as sulfonamides, anticonvulsants, allopurinol, nonsteroidal anti-inflammatory drugs, and antimalarials (Roujeau et al., N. Engl. J. Med., 333(24):1600-1607, 1995). In Taiwan, anticonvulsants (e.g., CBZ, phenytoin and phenobarbital) and allopurinol are the most common drugs causing SJS/TEN.
Recent developments of pharmacogenomics have implied that the susceptibility to ADRs is associated with particular genetic alleles. For example, genomic polymorphisms of the thiopurine methyltransferase gene were found to be closely related to ADRs induced by azathioprine, a drug for rheumatologic diseases or cancer (Yates et al., Ann. Intern. Med., 126(8):608-614, 1997). It is also suggested that the susceptibility to SJS/TEN/HSS induced by certain drugs is genetically determined (Gennis M A, Am. J. Med., 91(6):631-634, 1991; Edwards S G, Postgrad. Med. J., 75(889):680-681, 1999). However, the exact responsible genetic factors have yet to be identified.
These pharmacogenomics studies suggest that detecting ADR-associated alleles in a patient is a useful approach for assessing whether that patient is at risk for developing ADRs. This kind of molecular diagnostics certified by Clinical Laboratory Improvement Amendments is now offered by reference laboratories in the US and Europe.
To determine the presence of a particular genetic allele, one or more allelic-specific nucleotide need to be detected. In many cases, multiple regions within the allele must be targeted to achieve an accurate determination. For example, currently available methods for determining an HLA-B allele (e.g., HLA-B*1502 or HLA-B*5801) requires detecting at least 6 regions within that allele.